[unreadable] The collaborative project proposed in this FIRCA application is an extension of the project funded by parent grant CA 42471 ("Role of bZIP proteins in lymphocyte function"). The long-term objectives of the parent grant are to define the functions of the NFAT family of transcription factors, and their transcription partners AP-1 (Fos/Jun), in lymphocytes and other cell types. There is strong evidence that NFAT proteins regulate lymphocyte proliferation and differentiation as well as cell cycle progression, apoptosis and oncogenesis in lymphocytes and other cell types. The objective of this collaborative FIRCA proposal is to investigate the involvement of NFAT proteins in lymphoproliferative disease and oncogenic transformation of lymphocytes and fibroblasts. As part of the parent grant, a large number of reagents have been or are currently being generated, including constitutively-active NFAT proteins, gene-targeted mice lacking specific NFAT proteins, and gene-targeted mice conditionally expressing the constitutively-active NFAT proteins. In Aim 1, the lymphoproliferative phenotype of NFATI-/- mice will be analyzed, asking specifically whether the splenomegaly and lymphadenopathy of NFATI-/- mice are associated with any malignant transformation of lymphocytes and whether polyclonal stimulation of lymphocytes in these mice might trigger such malignant transformation. We will also ask whether lack of NFAT1 promotes cancer development upon exposure to chemical carcinogens, and whether lack of NFAT1 influences the rate and extent of cancer development in selected cancer-prone mouse strains. In Aim 2, the relationship between lymphocyte transformation and Thl/Th2 cytokine expression will be examined, by repeating the experiments of Aim 1 in mice lacking either IL-4, IFN-gamma or the IFN-gamma-induced transcription factor STATI. In Aim 3, the oncogenic potential of NFAT1 and NFAT2 will be compared in lymphocytes, in fibroblasts, and in vivo, in light of evidence that these two closely-related transcription factors may have tumor suppressor and oncogenic potential respectively. The results should provide new insights into NFAT function and may have important therapeutic implications, particularly if we find that NFAT selectively modulates oncogenic or cell death programs in lymphocytes. [unreadable] [unreadable]